Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature

Abstract

Gaucher disease type I, the most common lysosomal storage disorder, is associated with immunoglobulin abnormalities. We studied the prevalence, risk factors, pathogenesis, and effect of enzyme relation therapy (ERT) on gammopathies in an adult Gaucher disease type I cohort (N = 63) and related the results to a review of the currently available literature. Polyclonal gammopathies and monoclonal gammopathy of undetermined significance (MGUS) in our adult GD I cohort were found in 41% and 19% of patients. These results are similar to the data from the literature and correspond to the increased risk of multiple myeloma (MM) that has been described. The prevalence of MGUS in our cohort increased with age but was not associated with disease severity or exposure time. The serum levels of free light chains of immunoglobulins were measured and were not found predictive for the development of MGUS or MM. Levels of pro- as well as anti-inflammatory cytokines, growth factors, and chemokines, especially those involved in inflammation and B-cell function, are disturbed in GD I, with the most impressive and consisting elevations for interleukin-10 and pulmonary and activation-regulated chemokine. A beneficial effect of ERT on the occurrence and progression of gammopathies was suggested from longitudinal data.

Mesenchymal gaucho homing on the range

“…Of particular relevance to the process of FL transformation is whether the transformed lymphoma arises directly from FL, or might arise from additional genetic events in a lymphoma progenitor cell. Such a model is supported in findings by Carlotti et al 4 and those of Ruminy et al 5 wherein intraclonal diversity, as defined by the patterns of somatic hypermutation occurring in FL and transformed lymphoma, is more complex than previously described.…”

“…Other proinflammatory cytokines that influence bone homeostasis, B-cell differentiation, and plasma cell growth are variably abnormal in GD1 patients. 5 Proinflammatory macrophages that are recruited by and cluster with Gaucher cells are a likely source, but involvement by other cells is theoretically possible.…”

“…Increased blood levels of macrophage-derived osteoclastogenic cytokines MIP-␣ and MIP-␤ may also contribute to both general and focal GD1 skeletal manifestations. 5 As to myeloma and lymphoma, hypotheses have focused on the sphingolipid storage process itself as contributory to chronic antigenic stimulation or as an autocrine and/or paracrine stimulus to the production of cytokines and cellular growth factors. 1 Abnormal T-cell lectin responses and decreased numbers of CD4, NK, and dendritic cells have been reported.…”

Severe Impairment of Regulatory T-Cells and Th1-Lymphocyte Polarization in Patients with Gaucher Disease

“…Laboratory findings include elevated levels of acute-phase proteins (Rogowski et al 2005) and serum immunoglobulin levels (de Fost et al 2008), frequent occurrence of monoclonal gammopathy (Arends et al 2013), detection of various autoantibodies in patients' serum (Shoenfeld et al 1995), and increased plasma levels of proinflammatory cytokines, including IL-1b, IL-6, IL-8, IL-10, TNF-a, and TGF-b (Allen et al 1997;Barak et al 1999;Michelakakis et al 1996;Deegan et al 2005;Pérez Calvo et al 2000). These findings imply that chronic inflammatory status possibly reflects a chronic stimulation of the immune system.…”

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

“…Gaucher disease type 1 is the most frequent form of the disease and causes hepatosplenomegaly, bone marrow dysfunction, and skeletal disease and can be treated to different extents by enzyme replacement therapy and by substrate reduction therapy. There are also increased cytokines such as interleukin-1␤ (IL-1␤), IL-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), IL-6, IL-8, IL-10, IL-18, 2 hepatocyte growth factor (HGF), macrophage colony-stimulating factor (M-CSF), macrophage-inflammatory protein 1 (MIP-1), 3 CCL18/ PARC (pulmonary and activation-regulated chemokine), soluble CD14 (sCD14), transforming growth factor-␤1 (TGF-␤1), 2 and tumor necrosis factor-␣ (TNF-␣) levels (see de Fost et al 4 for more references). Some of these increases are inconstant between studies or patients and are not always correlated with clinical severity.…”